Neuroserpin: structure, function, physiology and pathology

Abstract

Neuroserpin is a serine protease inhibitor identified in a search for proteins implicated in neuronal axon growth and synapse formation. Since its discovery over 30 years ago, it has been the focus of active research. Many efforts have concentrated in elucidating its neuroprotective role in brain ischemic lesions, the structural bases of neuroserpin conformational change and the effects of neuroserpin polymers that underlie the neurodegenerative disease FENIB (familial encephalopathy with neuroserpin inclusion bodies), but the investigation of the physiological roles of neuroserpin has increased over the last years. In this review, we present an updated and critical revision of the current literature dealing with neuroserpin, covering all aspects of research including the expression and physiological roles of neuroserpin, both inside and outside the nervous system; its inhibitory and non-inhibitory mechanisms of action; the molecular structure of the monomeric and polymeric conformations of neuroserpin, including a detailed description of the polymerisation mechanism; and the involvement of neuroserpin in human disease, with particular emphasis on FENIB. Finally, we briefly discuss the identification by genome-wide screening of novel neuroserpin variants and their possible pathogenicity.

Serpin family proteins as potential biomarkers and therapeutic drugs in stroke: A systematic review and meta‐analysis on clinical/preclinical studies

“…Neuroserpin may inhibit NMDA activation and calcium accumulation in neurons induced by tPA 56,57 . The mechanism underlying its neuroprotective role is still debated, including both tPA‐dependent and tPA‐independent pathways 58 . It helps maintain the structure of BBB, protect neurons/astrocytes, and suppress neuroinflammatory responses such as microglial activation after stroke 59 .…”

An Unusual Case of Progressive Myoclonic Epilepsy (PME): Familial Encephalopathy with Neuroserpin Inclusion Body (FENIB)

“…In our case, the pathogenic variant c1175G > A (p.Gly392Glu) mutation in exon 9 is one of the very few cases reported worldwide and the first one from the Indian subcontinent. [6][7][8][9][10] In a transgenic mouse model this p. Gly392Glu mutation showed aggregation of neuroserpin in the endoplasmic reticulum and lysosomes of neurons creating neuroserpin inclusion bodies, also known as Collin bodies (periodic acid-Schiff positive, diastase resistant, and stains darkly with Heidenhain-Woelcke method). 11 In conclusion, we describe here a very rare case of PME associated with neuroserpin inclusion bodies and a G392E mutation in the SERPINI1 gene.…”

Neuroserpin, a crucial regulator for axogenesis, synaptic modelling and cell–cell interactions in the pathophysiology of neurological disease

“…The molecular basis for FENIB manifestation was initially suggested to be based on a loop–sheet model, which proposed that the RCL of one mutant neuroserpin molecule, inserted into the β-sheet-A of another mutant neuroserpin molecule, resulting in the formation and accumulation of loop–sheet polymeric structures within the endoplasmic reticulum (ER) of neuronal cells [ 30 , 107 ]. However, the formation of serpin polymers is currently hypothesised to be mediated by domain-swapping of the carboxyl-terminal ends of the mutant serpin molecules [ 26 , 40 , 169 ]. Yet despite these developments, the crystal structure of polymerised neuroserpin remains to be established for a better understanding of FENIB neuropathology.…”